The Efavirenz (EFV) Central Nervous System Exposure Sub-study of Encore1 (ENCORE1-CNS)

This study has been completed.
Sponsor:
Collaborator:
Imperial College London
Information provided by (Responsible Party):
Kirby Institute
ClinicalTrials.gov Identifier:
NCT01451333
First received: January 5, 2011
Last updated: May 10, 2013
Last verified: May 2013
  Purpose

Persistent HIV infection in the central nervous system (CNS) compartment may put subjects at risk of developing HIV-related brain disease. Important factors associated with the development of HIV-related brain disease include therapeutic concentrations of antiretroviral drugs in the CNS. Conflicting evidence regarding the CNS exposure of the antiretroviral drug used for the encore1 study, efavirenz (EFV) have been described in related studies. There were recent study of two small series assessment of EFV exposure in the cerebral spinal fluid (CSF); one group reported small detectable EFV concentrations, while another observed undetectable EFV exposure in the CSF. Also, in a larger reported series comprising of 80 subjects on EFV-containing antiretroviral therapy, a CSF to plasma concentration suggested that there is limited movement of EFV out of the CSF. In HIV-1 infected subjects at steady state, EFV plasma level parameters are dose proportional following 200mg, 400mg, and 600mg daily doses. The CNS exposure of EFV at different daily dosing has not been described.


Condition Intervention Phase
HIV Infection
Drug: Efavirenz
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: The EFV Central Nervous System Exposure Sub-study of Encore1: A Randomised, Double-blind, Placebo-controlled, Clinical Trial to Compare the Safety and Efficacy of Reduced Dose Efavirenz (EFV) With Standard Dose EFV Plus Two Nucleotide Reverse Transcriptase Inhibitors (N(t)RTI) in Antiretroviral-naïve HIV-infected Individuals Over 96 Weeks

Resource links provided by NLM:


Further study details as provided by Kirby Institute:

Primary Outcome Measures:
  • comparison of mean CSF concentration of EFV from both doses after week 24. [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
    measure the CSF exposure of EFV when dosed at 400mg and 600mg daily. Efavirenz plasma and CSF concentrations will be analysed and CSF:plasma ratios will be compared. Associations between plasma and CSF concentrations and relationship to study clinical parameters will be assessed.


Secondary Outcome Measures:
  • CSF EFV exposure and plasma exposure (CSF:plasma ratio) using statistical analysis [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
    The relationship between CSF EFV exposure and plasma exposure (CSF:plasma ratio), both for protein bound and free plasma EFV exposure.

  • The relationship between CSF EFV exposure and neuropsychiatric side effects using questionnaires and medical assessments [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • The relationship between CSF EFV exposure and other study parameters such as race and sex. [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • The number of subjects with EFV CSF exposure greater than the postulated CSF IC50 for wild type virus (0.51ng/mL) [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • CSF HIV RNA measurement after 12 - 24 weeks of study therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • Relationship between plasma HIV RNA and CSF HIV RNA [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • CSF biomarker analysis after 12 - 24 weeks of study therapy [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]
  • comparison between magnetic resonance (MR) spectroscopy findings and CSF HIV RNA and EFV concentration [ Time Frame: 24 weeks ] [ Designated as safety issue: Yes ]

Enrollment: 32
Study Start Date: September 2011
Study Completion Date: February 2013
Primary Completion Date: October 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Reduced dose Efavirenz arm
Patient's on main study that was randomised to receive TDF (300mg qd)/FTC (200mg qd) + EFV (400mg qd; 2 x 200mg + 1 x 200mg placebo qd).
Drug: Efavirenz
400mg qd; 2 x 200mg
Active Comparator: Normal Efavirenz dose arm
Patient's on main study randomised to receive tenofovir (TDF) (300mg qd)/emtricitabine (FTC) (200mg qd) + EFV (600mg qd; 3 x 200mg qd)
Drug: Efavirenz
600mg qd; 3 x 200mg qd

  Eligibility

Ages Eligible for Study:   16 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • All subjects entering into the main study protocol at participating centres will be eligible to enter this sub-study.

Exclusion Criteria:

  • Existing neurological disease which in the opinion of the investigator would be a contra-indication to lumbar puncture examination
  • CNS opportunistic infections in the past 12 weeks of randomisation
  • Bacterial or viral meningitis in the past 12 weeks of randomisation
  • Head injury requiring medical assessment in the past 12 weeks of randomisation
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01451333

Locations
Germany
Medical Group Practice
Berlin, Germany, 10777
Thailand
HIVNAT Research Collaboration
Patumwan, Bangkok, Thailand, 10330
Khon Kaen University
Khon Kaen, Thailand, 40002
United Kingdom
Imperial College, St. Mary's Hospital
Clinical Trials Centre, Winston Churchil Wing, London, United Kingdom, W2 1NY
Chelsea and Westminster Hospital
HIV/GUM laboratory 5th floor St. Stephen Centre, London, United Kingdom, SW10 9NH
Sponsors and Collaborators
Kirby Institute
Imperial College London
Investigators
Principal Investigator: Alan Winston, Dr. Imperial College London
  More Information

No publications provided

Responsible Party: Kirby Institute
ClinicalTrials.gov Identifier: NCT01451333     History of Changes
Other Study ID Numbers: NCHECR-ENCORE1-CNS
Study First Received: January 5, 2011
Last Updated: May 10, 2013
Health Authority: Australia: Therapeutic Goods Administration
United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Kirby Institute:
HIV
Efavirenz
Central Nervous System (CNS)
Lumbar puncture
Dose reduction

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Reverse Transcriptase Inhibitors
Efavirenz
Nucleic Acid Synthesis Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Anti-Retroviral Agents
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on August 26, 2014